PROJECT SUMMARY The tubulo-acinar network is the defining feature of the lacrimal gland structure, which is critical for its tear producing function. However, little is known on how this architecture is constructed at the molecular level. The project will investigate the novel role of non-receptor tyrosine kinase Csk in lacrimal gland lumen formation and cell differentiation. By generating inducible mouse mutants, we will define the timing and lineage specific function of Csk in acinar and ductal cells. Using both gain- and loss-of-function approaches, we seek to demonstrate that Src family kinases mediate Csk signaling in the lacrimal gland. We will also establish a chemical genetic system to examine the focal adhesion complex after acute inactivation of Csk and establish the role of cytoskeletal signaling in mediating Csk function in lacrimal gland development. Finally, we will elucidate the mechanism by which Csk signaling regulates the cellular transcriptome. Lacrimal gland dysfunction is the underlying cause of aqueous deficient dry eye diseases, which afflict millions of people. By elucidating the mechanism of Csk in generating the lacrimal gland, it will inform the development of cell based therapy for dry eye diseases.